JP5000495B2 - Substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides - Google Patents

Description

  The present invention relates to substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides, processes for their preparation, pharmaceutical preparations containing these compounds, and the use of these compounds in the manufacture of pharmaceutical preparations .

  Pain is a basic clinical symptom. There is a worldwide demand for effective pain treatment. The urgent need for treatment methods that provide targeted treatments tailored to individual cases of chronic and non-chronic pain is understood to mean effective and satisfactory pain treatment from the patient's standpoint, but applied analgesia, And many scientific papers on basic nociceptive studies that have recently emerged.

  Conventional opioids, such as morphine, are effective in treating severe to very severe pain, but exhibit undesirable accompanying symptoms such as respiratory distress, vomiting, sedation or constipation. Research into other pain relieving agents has been made worldwide.

  The object of the present invention is therefore to provide novel active ingredients which are particularly suitable as pharmacologically active ingredients for use in pharmaceutical preparations, preferably pharmaceutical preparations for treating pain.

  This object is achieved by providing substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to the invention of general formula I

  Surprisingly, substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to the invention of the general formula I below show high affinity for opioid receptors, in particular μ opioid receptors, and thus It has been found to be suitable for modulating the receptors.

  Substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to the invention of general formula I below further regulate, preferably inhibit, and 5-hydroxytryptamine (5-HT) uptake of noradrenaline (NA). Suitable for the regulation, preferably inhibition.

  Accordingly, the substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the following general formula I according to the present invention are pharmaceuticals for the prevention and / or treatment of disorders or diseases associated with the above receptors or processes. It can be used in particular as a pharmacologically active ingredient in a formulation.

  Accordingly, the present invention provides substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of general formula I:

(Where
R ¹ and R ² are saturated or unsaturated, unsubstituted or at least monosubstituted alicyclic residues, optionally with at least one further ring, together with the nitrogen atom that joins them as ring members. Forming the alicyclic residue containing a heteroatom as a ring member;

R ³ is a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic residue; a saturated or unsaturated, unsubstituted or at least monosubstituted alicyclic residue. The alicyclic residue optionally containing at least one heteroatom as a ring member and bonded via a linear or branched alkylene group; or unsubstituted or at least monosubstituted An aryl or heteroaryl residue, which may be linked via a linear or branched alkylene group,

R ⁴ is a hydrogen residue; a linear or branched, saturated or unsaturated unsubstituted aliphatic residue; a saturated or unsaturated, unsubstituted or at least monosubstituted alicyclic residue, The alicyclic residue which may contain at least one heteroatom as a ring member and may be bonded via a linear or branched alkylene group; or a linear or branched alkylene group An unsubstituted or at least monosubstituted aryl or heteroaryl residue attached via

R ⁵ is a linear or branched, saturated or unsaturated unsubstituted aliphatic residue; a saturated or unsaturated, unsubstituted or at least monosubstituted alicyclic residue, optionally at least 1 An alicyclic residue which may contain a heteroatom as a ring member and which may be bonded via a linear or branched alkylene group; or bonded via a linear or branched alkylene group An unsubstituted or at least monosubstituted aryl or heteroaryl residue,

Or
R ⁴ and R ⁵ are saturated or unsaturated, unsubstituted or at least monosubstituted alicyclic residues, optionally with at least one further ring, together with the nitrogen atom connecting them as ring members. Forming the alicyclic residue containing a hetero atom as a ring member)

In each case, optionally in their pure stereoisomers, in particular enantiomers or diastereomers, their racemates, mixtures of stereoisomers in any desired mixing ratio, in particular enantiomers, diastereomers and It may be in the form of a mixture of rotamers or in each case the corresponding salt form or in each case the corresponding solvate form.

A compound of general formula I,
-R ¹ and R ² are piperazinyl residues, together with the nitrogen atom that binds them as ring members, and are substituted with o- (iso-propyloxy) -phenyl residue on the other nitrogen atom at the 4-position A compound in the form of a fumarate salt, wherein R ³ represents a methyl residue, R ⁴ represents a hydrogen residue, and R ⁵ represents an iso-propyl residue,
-R ¹ and R ² are piperazinyl residues, together with the nitrogen atom that binds them as ring members, and are substituted with o- (iso-propyloxy) -phenyl residue on the other nitrogen atom at the 4-position A compound in the form of a fumarate salt, wherein R ³ represents a methyl residue, R ⁴ represents a hydrogen residue, and R ⁵ represents a methyl residue,
-R ¹ and R ² are piperazinyl residues, together with the nitrogen atom that binds them as ring members, and are substituted with o- (iso-propyloxy) -phenyl residue on the other nitrogen atom at the 4-position A piperazinyl residue, R ³ represents a methyl residue, and R ⁴ and R ⁵ together with the nitrogen atom connecting them form a piperidinyl residue, a compound in the form of a hydrochloride hydrate,
-R ¹ and R ² together with the nitrogen atom connecting them as ring members are piperazinyl residues, and the piperazinyl residue substituted on the other nitrogen atom at the 4-position with an o- (methoxy) -phenyl residue A compound in the form of a fumarate salt, R ³ represents a methyl residue, R ⁴ represents a hydrogen residue, and R ⁵ represents a methyl residue,
Are preferably excluded.

A compound of general formula I,
-R ¹ and R ² are piperazinyl residues, together with the nitrogen atom that binds them as ring members, and are substituted with o- (iso-propyloxy) -phenyl residue on the other nitrogen atom at the 4-position A compound that forms a piperazinyl residue, R ³ represents a methyl residue, R ⁴ represents a hydrogen residue, and R ⁵ represents an iso-propyl residue,
-R ¹ and R ² are piperazinyl residues, together with the nitrogen atom that binds them as ring members, and are substituted with o- (iso-propyloxy) -phenyl residue on the other nitrogen atom at the 4-position A compound that forms a piperazinyl residue, R ³ represents a methyl residue, R ⁴ represents a hydrogen residue, and R ⁵ represents a methyl residue,
-R ¹ and R ² are piperazinyl residues, together with the nitrogen atom that binds them as ring members, and are substituted with o- (iso-propyloxy) -phenyl residue on the other nitrogen atom at the 4-position A compound that forms a piperazinyl residue, R ³ represents a methyl residue, and R ⁴ and R ⁵ together with the nitrogen atom to which they are attached,
-R ¹ and R ² together with the nitrogen atom connecting them as ring members are piperazinyl residues, and the piperazinyl residue substituted on the other nitrogen atom at the 4-position with an o- (methoxy) -phenyl residue A compound wherein R ³ represents a methyl residue, R ⁴ represents a hydrogen residue, and R ⁵ represents a methyl residue;
And in each case its corresponding salt and in each case its corresponding hydrate are particularly preferably excluded.

Preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention are those in which the residues R ¹ and R ² are
Saturated or unsaturated, unsubstituted or at least monosubstituted 4-, 5-, 6-, 7-, 8- or 9-membered alicyclic residues with nitrogen atoms connecting them as ring members Optionally forming said alicyclic residue comprising at least one further heteroatom as a ring member,

4-, 5-, 6-, 7-, 8- or 9-membered alicyclic residues, optionally saturated or unsaturated, with nitrogen atoms connecting them as ring members, optionally Forming an alicyclic residue containing at least one further heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as a ring member, wherein the alicyclic residue is C _1-5 alkyl, -C (= O) -OC _1-5 -alkyl, -OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH ₂ , -C (= O) -NH-C _1-5- Alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , the same or different substituents selected from the group consisting of furanyl, thiophenyl, pyridinyl, phenyl and benzyl, wherein the cyclic substituent is itself unsubstituted or at least monosubstituted May be mono- or polysubstituted,

Together with the nitrogen atom connecting them as ring members, particularly preferably form imidazolidinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, morpholinyl or thiomorpholinyl residues, these residues being C _1-5 alkyl, -C (= O) -OC _1-5 -alkyl, OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH ₂ , -C (= O) -NH-C _{1 -5} -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl The same or different substituents selected from the group consisting of, -N (C _1-5 -alkyl) ₂ , furanyl, thiophenyl, pyridinyl, phenyl and benzyl, wherein the cyclic substituent is itself unsubstituted or at least May be mono- or poly-substituted)

And in each case, the residues R ³ to R ⁵ have the meanings given above, and in each case, in some cases their pure stereoisomers, in particular enantiomers or diastereomers, their racemates, any desired In the form of a mixture of stereoisomers, in particular a mixture of enantiomers, diastereomers and / or rotamers, or in each case the corresponding salt form or in each case the corresponding solvate form, It is a good compound.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention are those in which the residue R ³ is linear or branched, saturated or unsaturated, unsubstituted or at least _{Monosubstituted} aliphatic C _1-10 residues; saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered fats A cyclic residue, optionally containing at least one heteroatom as a ring member and optionally linked via a linear or branched C _1-3 alkylene group Or an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue which may be bonded via a linear or branched C _1-3 alkylene group, or Represents a heteroaryl residue,

Preferably a linear or branched unsubstituted or at least monosubstituted C _1-5 alkyl residue; a saturated or unsaturated, unsubstituted or at least monosubstituted 4-, 5-, 6-, 7-, An 8- or 9-membered alicyclic residue which may be linked via a linear or branched C _1-3 alkylene group; or unsubstituted or at least one A substituted 5- or 6-membered aryl or heteroaryl residue, which may be linked via a linear or branched C _1-3 alkylene group ,

Particularly preferably, it represents an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl,
And in each case, the residues R ¹ , R ² , R ⁴ and R ⁵ have the meanings given above, and in each case, in some cases, their pure stereoisomers, especially enantiomers or diastereomers, their Racemates, mixtures of stereoisomers in any desired mixing ratio, in particular in the form of mixtures of enantiomers, diastereomers and / or rotamers, or in each case the corresponding salt form, or in each case the corresponding solvation A compound that may be in the form of a product.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention are those wherein R ⁴ is a hydrogen residue; linear or branched, saturated or unsaturated unsubstituted fat Group C _1-10 residues; saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered alicyclic residues The alicyclic residue optionally containing at least one heteroatom as a ring member and linked via a linear or branched C _1-3 alkylene group; or Represents an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue attached via a branched C _1-3 alkylene group;

Preferably a hydrogen residue; a linear or branched unsubstituted C _1-5 alkyl residue; an unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7- , An 8- or 9-membered alicyclic residue; or an unsubstituted or at least monosubstituted phenyl residue attached via a linear or branched C _1-3 alkylene group;

Particularly preferably a hydrogen residue; an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl; cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, cycloheptyl or cyclooctyl residues; or an unsubstituted or at least monosubstituted benzyl residue;
And in each case the residues R ¹ to R ³ and R ⁵ , and R ⁴ and R ⁵ both have the meanings given above, and in each case, in some cases, their pure stereoisomers, especially enantiomers or diastereoisomers Isomers, their racemates, mixtures of stereoisomers in any desired mixing ratio, in particular in the form of enantiomers, diastereomers and / or rotamers, or in each case the corresponding salt forms or in each case corresponding It may be in the form of a solvate.

Further preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention are those wherein R ⁵ is a linear or branched, saturated or unsaturated unsubstituted aliphatic C _{1- 10} residues; saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered alicyclic residues The alicyclic residue which contains at least one heteroatom as a ring member and may be linked via a linear or branched C _1-3 -alkylene group; or linear or branched C _{1-3 represents} an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue linked via an alkylene group;

Preferably linear or branched, unsubstituted C _1-5 alkyl residue; unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- Or a 9-membered alicyclic residue; or an unsubstituted or at least monosubstituted phenyl residue linked via a linear or branched C _1-3 alkylene group,

Particularly preferably an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo A heptyl or cyclooctyl residue; or an unsubstituted or at least monosubstituted benzyl residue, and in each case the residues R ¹ to R ⁴ , and R ⁴ and R ⁵ together have the above meaning In each case, in some cases their pure stereoisomers, especially enantiomers or diastereomers, their racemates, mixtures of stereoisomers in any desired mixing ratio, especially enantiomers, diastereomers and / or rotations In the form of a mixture of isomers, or in each case the corresponding salt form or in each case the corresponding solvate form. It is also may compound.

Likewise preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula according to the invention are those in which R ⁴ and R ⁵ are saturated or unsaturated, together with the nitrogen atom to which they are attached as a ring member. An unsubstituted or at least monosubstituted 4-, 5-, 6-, 7-, 8- or 9-membered alicyclic residue, optionally ringed with at least one additional heteroatom Forming the alicyclic residue to include as a member,

Preferably a saturated or unsaturated 4-, 5-, 6-, 7-, 8- or 9-membered alicyclic residue with nitrogen atoms connecting them as ring members, optionally nitrogen Forming an alicyclic residue containing as a ring member at least one further heteroatom selected from the group consisting of oxygen and sulfur, wherein the alicyclic residue is C _1-5 alkyl, -C (= O) -OC _1-5 -alkyl, -OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH _2, -C (= O) -NH-C _1-5- Alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , the same or different substituents selected from the group consisting of furanyl, thiophenyl, pyridinyl, phenyl and benzyl, wherein the cyclic substituent is itself unsubstituted or at least monosubstituted May be mono- or polysubstituted,

Together with the nitrogen atom connecting them as ring members, particularly preferably form imidazolidinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, morpholinyl or thiomorpholinyl residues, which are C _1-5 alkyl, -C ( = O) -OC _1-5 -alkyl, -OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH _2, -C (= O) -NH-C _1-5 -Alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl,- The same or different substituents selected from the group consisting of N (C _1-5 -alkyl) ₂ , furanyl, thiophenyl, pyridinyl, phenyl and benzyl, wherein the cyclic substituent is itself unsubstituted or at least monosubstituted And in each case the residues R ¹ to R ³ , R ⁴ and R ⁵ are independent of one another. In each case in some cases their pure stereoisomers, in particular enantiomers or diastereomers, their racemates, mixtures of stereoisomers in any desired mixing ratio, in particular enantiomers, A compound which may be in the form of a mixture of diastereomers and / or rotamers, or in each case the corresponding salt form or in each case the corresponding solvate form.

When R ³ is a linear or branched, saturated or unsaturated aliphatic residue, ie a linear or branched alkyl, alkenyl or alkynyl residue, which is mono- or polysubstituted, for example When mono-, di-, _3- , 4- or 5-substituted, the substituents are preferably independently of each other halogen, hydroxy, -CN, -CF ₃ , -CHF ₂ , -CH ₂ F, C Especially preferred may be selected from the group consisting of _1-5 alkoxy, —NH ₂ , —NH—C _1-5 -alkyl, —N (C _1-5 -alkyl) ₂ , and optionally at least monosubstituted phenyl. May be selected from the group consisting of F, Cl, Br and hydroxy. When the phenyl substituent itself is mono- or poly-substituted, for example when it is mono-, di-, tri-, 4- or 5-substituted, the substituents are preferably independently of one another preferably hydroxy, F, Cl, _{br, I, -NH 2, -NH} -C 1-5 - alkyl, -N (C _1-5 - _{alkyl) 2, -C (= O)} -NH 2, -C (= O) -NH-C _1-5 - alkyl, -C (= O) -N ( C 1-5 - _{alkyl) 2, -NO 2, -CN,} -CF 3, -CHF 2, -CH 2 F, C 1-5 alkyl and It may be selected from the group consisting of C _1-5 alkoxy.

Examples of suitable alkyl, alkenyl and alkynyl residues which may be mono- or polysubstituted, for example mono-, di-, tri-, tetra- or penta-substituted are methyl, ethyl, n-propyl , Iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, 1-hexyl, n-heptyl, n-octyl, n-nonyl , N-decyl, -C (H) (C ₂ H ₅ ) ₂ , -C (H) (nC ₃ H ₇ ) ₂ , -CH ₂ -CH ₂ -C (H) (CH ₃ )-(CH ₂ ) ₃ -CH ₃ , vinyl, ethynyl, propenyl, allyl, propynyl, butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl.

A monocyclic alicyclic residue formed by R ¹ and R ² together with a nitrogen atom that binds R ¹ and R ² as ring members, optionally including at least one additional heteroatom as ring member, Saturated or unsaturated but not aromatic. The residues may be mono- or polysubstituted with the same or different substituents, e.g. mono-, di-, tri-, tetra- or penta-substituted, wherein the substituents are independent of each other. Preferably C _1-5 alkyl, -C (= O) -OC _1-5 -alkyl, -OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH ₂ , -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , furanyl, thiophenyl, phenyl, pyridinyl and benzyl, particularly preferably methyl, ethyl, n-propyl, iso -Propyl, -C (= O) -O-CH ₃ , -C (= O) -OC ₂ H ₅ , -C (= O) -O- (nC ₃ H ₇ ), -C (= O)- It may be selected from the group consisting of O- (iso-C ₃ H ₇ ), and optionally phenyl bonded via a — (CH ₂ ) group. Each furanyl, thiophenyl, pyridinyl, phenyl or benzyl substituent may itself be mono- or poly-substituted in the ring system and may optionally be mono-, di-, tri-, tetra- or penta-substituted. Well, where the substituents are independently of one another, preferably hydroxy, F, Cl, Br, I, —NH ₂ , —NH—C _1-5 -alkyl, —N (C _1-5 -alkyl) ₂ , -C (= O) -NH ₂ , -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -NO ₂ ,- It may be selected from the group consisting of CN, —CF ₃ , —CHF ₂ , —CH ₂ F, C _1-5 alkyl and C _1-5 alkoxy.

If the residues R ⁴ and R ⁵ together with the nitrogen atom to which they are attached as a ring member form an alicyclic residue optionally containing at least one further heteroatom as a ring member, this monocyclic The residue may be saturated or unsaturated but not aromatic. The residues may be mono- or polysubstituted with the same or different substituents, e.g. mono-, di-, tri-, tetra- or penta-substituted, wherein the substituents are independent of each other. Preferably C _1-5 alkyl, -C (= O) -OC _1-5 -alkyl, -OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH _2, -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , furanyl, thiophenyl, pyridinyl, phenyl and benzyl, particularly preferably methyl, ethyl, n-propyl, iso -Propyl, -C (= O) -O-CH ₃ , -C (= O) -OC ₂ H ₅ , -C (= O) -O- (nC ₃ H ₇ ), -C (= O)- It may be selected from the group consisting of O- (iso-C ₃ H ₇ ), and optionally phenyl bonded via a — (CH ₂ ) group. Each furanyl, thiophenyl, pyridinyl, phenyl or benzyl substituent may itself be mono- or poly-substituted and optionally mono-, di-, tri-, tetra- or penta-substituted, where in the substituent is preferably hydroxy, F, Cl, Br, I , -NH 2, -NH-C 1-5 - alkyl, -N (C _1-5 - _{alkyl) 2, -C (= O)} - _{NH 2, -C (= O)} -NH-C 1-5 - alkyl, -C (= O) -N ( C 1-5 - _{alkyl) 2, -NO 2, -CN,} -CF 3, -CHF ₂ , may be selected from the group consisting of —CH ₂ F, C _1-5 alkyl and C _1-5 alkoxy.

Residues R ¹ and R ² and / or residues R ⁴ and R ⁵ with one or more, for example 1, 2 or 3 heteroatoms as ring members, together with nitrogen atoms connecting them as ring members When forming alicyclic residues comprising, the heteroatoms may preferably be selected independently of one another from the group consisting of oxygen, nitrogen and sulfur unless otherwise stated.

Residues R ¹ and R ² and / or residues R ⁴ and R ⁵ together with the nitrogen atom to which they are attached as a ring member and optionally at least one further heteroatom as a ring member When forming a group, the alicyclic residue may be mono- or polysubstituted, for example mono-, di-, 3-, 4- or 5-substituted, which residue is preferably imidazolidinyl , Aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, morpholinyl and thiomorpholinyl.

If one or more of the residues R ³ to R ⁵ above represents a saturated or unsaturated alicyclic residue optionally containing at least one further heteroatom as a ring member, or the same or When containing alicyclic residues, mono-, poly-, optionally mono-, di-, tri-, tetra- or penta-substituted with different substituents, the corresponding substituents are independent of each other. Preferably C _1-5 alkyl, -C (= O) -OC _1-5 -alkyl, -OC _1-5 -alkyl, Cl, F, Br, I, -C (= O) -NH _2, -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -C (= O) -C _1-5 -alkyl, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , furanyl, thiophenyl, pyridinyl, phenyl and benzyl, particularly preferably methyl, ethyl, n-propyl , Iso-propyl, -C (= O) -O-CH ₃ , -C (= O) -OC ₂ H ₅ , -C (= O) -O- (nC ₃ H ₇ ), —C (═O) —O— (iso-C ₃ H ₇ ), and optionally phenyl may be selected via the — (CH ₂ ) group. When the furanyl, thiophenyl, pyridinyl, phenyl or benzyl substituents are themselves mono- or polysubstituted, optionally when they are mono-, di-, 3-, 4- or 5-substituted, the substituents are independently, preferably hydroxy, F, Cl, Br, I , -NH 2, -NH-C 1-5 - alkyl, -N (C _1-5 - _{alkyl) 2, -C (= O)} -NH ₂ , -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , -NO ₂ , -CN, -CF ₃ , -CHF ₂ , —CH ₂ F, C _1-5 alkyl and C _1-5 alkoxy. Unless stated otherwise, the heteroatoms may be independently selected from the group consisting preferably of oxygen, nitrogen and sulfur. Said alicyclic residue 1 or 2 may preferably contain further heteroatoms as ring members.

  Suitable alicyclic residues which may be mono- or polysubstituted, for example mono-, di-, tri-, tetra- or penta-substituted and may be mentioned by way of example are cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

  Cycloaliphatic residues containing one or more heteroatoms as ring members, which may be mono- or polysubstituted, eg mono-, di-, tri-, tetra- or penta-substituted Suitable and cycloaliphatic residues that may well be described by way of example are imidazolidinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, tetrahydrofuranyl (tetrahydrofuryl), morpholinyl, and thiomorpholinyl.

Corresponding if one or more of the above residues R ³ to R ⁵ contain mono- or poly-substituted, eg mono-, di-, ^3- , 4- or 5-substituted aryl residues The substituents are, in each case, independently of one another, preferably halogen, hydroxy, —CN, —CF ₃ , —CHF ₂ , —CH ₂ F, —NO ₂ , —NH ₂ , —NH—C _1-5 — Alkyl, -N (C _1-5 -alkyl) ₂ , -C (= O) -NH ₂ , -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , _C1-5alkyl , _C1-5alkoxy , and optionally at least monosubstituted phenyl, particularly preferably F, Cl, Br, hydroxy, -OCH _It can be selected from the group consisting of ₃ and —CH ₃ . When the phenyl substituent is itself mono- or polysubstituted, for example mono-, di-, 3-, 4- or 5-substituted, the substituent is preferably hydroxy, F, Cl, Br, I, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , -C (= O) -NH _2, -C (= O) -NH-C _1-5- alkyl, -C (= O) -N ( C 1-5 - _{alkyl) 2, -NO 2, -CN,} -CF 3, -CHF 2, -CH 2 F, C 1-5 alkyl and C _1-5 It may be selected from the group consisting of alkoxy.

  Suitable aryl residues which may be mono- or polysubstituted and which may be mentioned by way of example are phenyl, 1-naphthyl and 2-naphthyl.

If one or more of the above residues R ³ to R ⁵ contains a mono- or polysubstituted, eg 1-, ni-, ^3- , 4- or 5-substituted heteroaryl residue In each case independently of one another, preferably halogen, hydroxy, —CN, —CF ₃ , —CHF ₂ , —CH ₂ F, —NO ₂ , —NH ₂ , —NH—C _1-5 — Alkyl, -N (C _1-5 -alkyl) ₂ , -C (= O) -NH _2, -C (= O) -NH-C _1-5 -alkyl, -C (= O) -N (C _1-5 -alkyl) ₂ , _C1-5alkyl , _C1-5alkoxy , and optionally at least monosubstituted phenyl, particularly preferably F, Cl, Br, hydroxy, -OCH _It can be selected from the group consisting of ₃ and —CH ₃ . When the phenyl substituent itself is mono- or poly-substituted, for example when it is mono-, di-, tri-, 4- or 5-substituted, the substituent is preferably hydroxy, F, Cl, Br, I, -NH ₂ , -NH-C _1-5 -alkyl, -N (C _1-5 -alkyl) ₂ , -C (= O) -NH _2, -C (= O) -NH-C _1-5- alkyl, -C (= O) -N ( C 1-5 - _{alkyl) 2, -NO 2, -CN,} -CF 3, -CHF 2, -CH 2 F, C 1-5 alkyl and C _1-5 It may be selected from the group consisting of alkoxy. The heteroaryl residue is preferably monocyclic and contains 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

  Suitable heteroaryl residues that may be mentioned are, for example, pyrrolyl, indolyl, furyl (furanyl), benzo [b] furanyl, thienyl (thiophenyl), benzo [b] thienyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, triazolyl, Oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl and quinazolinyl.

The above C _1-5 alkyl and C _1-5 alkoxy residues may in each case be linear or branched. The C _1-5 alkyl residue includes the residues methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl and neopentyl. The C _1-5 alkoxy residues are the residues methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy and neopentoxy. Including.

Very particularly preferred substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides according to the invention are selected from the group consisting of:
1-methyl-5- (4-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzylmethylamide,
(5-azepan-1-ylmethyl-1-methyl-1H-pyrrol-2-yl) -pyrrolidin-1-ylmethanone,
[1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrol-2-yl] -pyrrolidin-1-ylmethanone,
1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carboxylic acid benzylamide,
1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzyl-methylamide,
1- (5-dibenzylcarbamoyl-1-methyl-1H-pyrrol-2-ylmethyl) -piperidine-4-carboxylic acid ethyl ester,
5- (4-benzyl-piperidin-1-ylmethyl) -1-methyl-1H-pyrrole-2-carboxylic acid cyclohexylmethylamide,
[5- (4-benzyl-piperidin-1-ylmethyl) -1-methyl-1H-pyrrol-2-yl] -piperidin-1-ylmethanone,
1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzylisopropylamide, and
1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrol-2-yl] -piperidin-1-ylmethanone,
Here, in each case, optionally in some cases their pure stereoisomers, in particular enantiomers or diastereomers, their racemates, mixtures of stereoisomers in any desired mixing ratio, in particular enantiomers, diastereomers And / or in the form of a mixture of rotamers, or in each case the corresponding salt form or in each case the corresponding solvate form.

  The present invention also provides a process for the preparation of substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of general formula I according to the invention, according to the process for the preparation of substituted 1H-pyrrole- 2-Carboxamide:

(Wherein the residues R ³ , R ⁴ and R ⁵ have the meanings given above) are preferably obtained using conventional methods known to those skilled in the art, preferably in suitable solvents such as CH ₂ Cl ₂ , CH ₃ CN, dimethylformamide (DMF), or a mixture of at least two of these solvents, at room temperature (about 20-25 ° C.), an iminium salt of general formula III:

Wherein R ¹ to R ² have the above meanings and A ⁻ is a suitable anion, preferably Cl ⁻ , AlCl ₄ ⁻ , Br ⁻ , I ⁻ or CF ₃ —SO ₃ ⁻ (triflate anion To produce a substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of general formula I according to the invention, and this latter compound is optionally known to those skilled in the art. Using conventional methods, preferably purified by extraction and optionally isolated.

  Compounds of general formula II can be prepared using conventional methods known to those skilled in the art, for example, AJ Carpenter, DJ Chadwick, Journal of Organic Chemistry, 1985, 50, pages 4362-4368, and TJ Donohoe, PM Guyo, Journal of As described in Organic Chemistry 1996, 61,7664-7665, for example, a commercially available reagent of the general formula IV:

Can be manufactured from. The corresponding literature description is incorporated herein by reference and is considered part of the present disclosure.

  Similarly, iminium salts of general formula III can also be prepared using conventional methods known to those skilled in the art, for example, H. Heaney, Tetrahedron 1997, 53, 2941-2958, and H. Heaney, Tetrahedron Lett. 1988, 29, As described on pages 2377-2380, for example, the corresponding aminals of the general formula V:

(Wherein the residues R ¹ and R ² have the meanings given above). The corresponding literature description is incorporated herein by reference and is considered part of the present disclosure.

  Aminals of the general formula V are also known from the literature, for example as described in H. Heaney, Tetrahedron 1997, 53, 2941-2958 and H. Heaney, Tetrahedron Lett. 1988, 29, 2377-2380. Can be manufactured using different methods. The corresponding literature description is incorporated herein by reference and is considered part of the present disclosure.

  The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention and the corresponding stereoisomers are not only in their free base or free acid form, but also in the corresponding salts, in particular physiological It can also be isolated in the form of an acceptable salt.

  The free bases of the 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention and the corresponding stereoisomers are, for example, inorganic or organic acids, preferably hydrochloric acid, hydrobromic acid , Sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid It can be converted to the corresponding salt, preferably a physiologically acceptable salt.

  The free bases of the 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention and the corresponding stereoisomers are preferably the compounds of the general formula I or the corresponding stereoisomers as free bases. The body can be converted to the corresponding hydrochloride salt by dissolving in a suitable organic solvent such as butan-2-one (methyl ethyl ketone) and combining with trimethylsilyl chloride (TMSCl).

  The free bases of 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I and the corresponding stereoisomers are likewise free acid or salts of sugar substitutes such as saccharin, ticlo or acesulfame. Salt and the corresponding physiologically acceptable salt.

  The respective free acids of the 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I and the corresponding stereoisomers can be reacted with the appropriate bases accordingly to the corresponding salts, in particular physiological Can be converted to an acceptable salt.

  The 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention and the corresponding stereoisomers are optionally similar to the corresponding acids, corresponding bases or salts of these compounds, It can be converted into its solvate, preferably its hydrate form, by conventional methods known to those skilled in the art.

  After the preparation of the substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I according to the invention, its stereoisomeric form, preferably its racemate or various enantiomers and / or diastereomers And / or if obtained in the form of other mixtures of rotamers, these may be separated and optionally isolated by conventional methods known to those skilled in the art. Examples which can be mentioned are chromatographic separation methods, in particular liquid phase chromatography methods at standard or high pressure, preferably MPLC and HPLC methods, and fractional crystallization methods. Diastereoisomers formed by individual enantiomers such as HPLC on chiral stationary phases or by crystallization with chiral acids such as (+)-tartaric acid, (-)-tartaric acid or (+)-10-camphorsulfonic acid The mer salts can in particular be separated from one another in the present application.

  The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I and the corresponding stereoisomers according to the invention and the corresponding acids, bases, salts and solvates in each case are toxicologically It is safe and therefore suitable as a pharmaceutically active ingredient for pharmaceutical preparations.

  Accordingly, the present invention further relates to at least one substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of general formula I according to the invention, optionally in its racemic form, one of its pure stereoisomers. , Especially in the form of enantiomers or diastereomers, or mixtures of stereoisomers of any desired mixing ratio, in particular enantiomers, diastereomers and / or rotamers, or in each case the corresponding salts, in particular physiologically acceptable Provided is a pharmaceutical formulation comprising a salt, particularly preferably a hydrochloride or a corresponding solvate, in particular a hydrate, and optionally a physiologically acceptable auxiliary substance.

  These pharmaceutical formulations of the invention comprise opioid receptor modulation, preferably μ opioid receptor modulation, noradrenaline (NA) uptake, preferably noradrenaline (NA) uptake, and 5-hydroxytryptamine (5 -HT) Particularly suitable for regulating intake, preferably for inhibiting 5-hydroxytryptamine (5-HT) intake.

  The pharmaceutical formulations of the invention are also preferably at least partly opioid receptors, in particular mu opioid receptors, and / or noradrenaline (NA) receptors and / or 5-hydroxytryptamine (5-HT) receptors. Suitable for prevention and / or treatment of mediated disorders or diseases.

  The pharmaceutical preparation of the invention is also preferably a pain cure, preferably a pain cure selected from chronic pain, acute pain and neuropathic pain; withdrawal symptoms, memory impairment, neurodegenerative diseases, preferably Parkinson's disease, Selected from the group consisting of Huntington's disease, Alzheimer's disease, and multiple sclerosis, epilepsy, cardiovascular disorders, water retention conditions, intestinal motility (diarrhea), urinary incontinence, loss of appetite, tinnitus, itching, Prevention and / or treatment of depression, sexual dysfunction, preferably erectile dysfunction, or airway disease; food intake disorders, preferably obesity, bulimia, anorexia, cachexia and type II diabetes (non-insulin dependent diabetes) Prevention and / or treatment of those selected from the group consisting of: or relief of anxiety; diuresis; suppression of the micturition reflex; reduction of the possibility of opioid addiction, preferably morphine addiction; Effects on the cardiovascular system, preferably vasodilation of the arteries; regulation of motor activity suitable for the regulation of or electrolyte balance.

  The pharmaceutical preparations according to the invention are particularly suitable for the treatment of pain, preferably pain selected from the group consisting of chronic pain, acute pain and neuropathic pain.

  The present invention also relates to one or more substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I, optionally in their pure stereoisomers, in particular enantiomers or diastereomers. , Its racemates, or mixtures of stereoisomers of any desired mixing ratio, in particular enantiomers, diastereomers and / or rotamers, or in each case the corresponding salts, in particular physiologically acceptable salts, particularly preferably Modulation of the opioid receptor of the substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide, preferably in the form of the hydrochloride salt, or in each case the corresponding solvate, in particular the hydrate. Regulation of opioid receptors, regulation of noradrenaline (NA) intake, preferably inhibition of noradrenaline (NA) intake, or regulation of 5-hydroxytryptamine (5-HT) intake, preferably 5-hydride Inhibition of carboxymethyl tryptamine (5-HT) uptake, provides for the manufacture of pharmaceutical formulations for.

  The present invention also relates to one or more substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I, optionally in their pure stereoisomers, in particular enantiomers or diastereomers. , Its racemates, or mixtures of stereoisomers of any desired mixing ratio, in particular enantiomers, diastereomers and / or rotamers, or in each case the corresponding salts, in particular physiologically acceptable salts, particularly preferably The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide in the form of the hydrochloride salt, or in each case the corresponding solvate, in particular the hydrate, is used for pain healing, preferably chronic pain, Healing of pain selected from acute pain and neuropathic pain; withdrawal symptoms, memory impairment, neurodegenerative diseases, preferably Parkinson's disease, Huntington's disease, Alzheimer's disease, and / or many Selected from the group consisting of sex sclerosis, epilepsy, cardiovascular disorders, water retention conditions, intestinal motility (diarrhea), urinary incontinence, loss of appetite, tinnitus, itching, depression, sexual dysfunction, preferably erection Prevention and / or treatment of insufficiency or airway disease; food intake disorders, preferably selected from the group consisting of obesity, bulimia, anorexia, cachexia and type II diabetes (non-insulin dependent diabetes) Prevention and / or treatment; or relief of anxiety; diuresis; suppression of the micturition reflex; reduction of the possibility of opioid addiction, preferably morphine addiction; modulation of locomotor activity; effects on the cardiovascular system, preferably arterial vasodilation; Or use in the manufacture of a pharmaceutical formulation for the regulation of electrolyte balance.

  The pharmaceutical formulations of the present invention can be used in liquid, semi-solid or solid dosage forms such as injectable solutions, drops, succis, syrups, sprays, suspensions, tablets, patches, capsules, dressings. Suppositories, ointments, creams, lotions, gels, emulsions, aerosols, or multiparticulate forms such as pellets or granules, optionally pressed into tablets, packaged in capsules, or suspended in liquids , And can be administered as is.

  One or more substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the general formula I, optionally in racemic form, in pure stereoisomers, in particular enantiomers or diastereomers Or a mixture of stereoisomers in any desired mixing ratio, in particular a mixture of enantiomers, diastereomers and / or rotamers, or in each case the corresponding salts, in particular physiologically acceptable salts, or corresponding solvates, In addition to the substituted 5-aminomethyl-1H-pyrrole-2-carboxylic amides, especially in the form of hydrates, the pharmaceutical formulations of the present invention are conventionally further physiologically acceptable Auxiliary material, preferably selected from the group consisting of matrix materials, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, slip agents, lubricants, fragrances and binders Including.

  The choice of physiologically acceptable auxiliary substances and the amount used thereof can be used for oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, or for example Depends on local administration by skin, mucous membrane and eye infection.

  Formulations in the form of tablets, coated tablets, capsules, granules, pellets, drops, solutions and syrups are preferred for oral administration, whereas solutions, suspensions, easily reconstituted dry formulations and sprays are parenteral, topical And preferred for inhalation administration.

  Substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of general formula I, optionally in racemic form, in pure stereoisomers, in particular enantiomers or diastereomers, or in any desired mixture A mixture of stereoisomers of a particular ratio, in particular a mixture of enantiomers, diastereomers and / or rotamers, or in each case a corresponding salt, in particular a physiologically acceptable salt, or a corresponding solvate, in particular a hydrate. The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides in the form are dissolved in a depot or dressing, optionally with the addition of a skin penetration enhancer What is contained therein is a suitable preparation for transdermal administration.

  Orally or transdermally administrable preparations are also certain substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of general formula I, optionally in racemic form, in pure form Stereoisomers, in particular enantiomers or diastereomers, or mixtures of stereoisomers in any desired mixing ratio, in particular mixtures of enantiomers, diastereomers and / or rotamers, or in each case the corresponding salts, in particular physiological The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides in the form of acceptable salts, or the corresponding solvates, especially hydrates, can be released slowly.

  The manufacture of the pharmaceutical formulations of the present invention can be accomplished by conventional means, devices, methods and processes known to those skilled in the art, such as AR Gennaro (ed.), “Remington's Pharmaceutical Sciences”, 17th edition, Mack Publishing Company, Easton, Pa. (1985), in particular with the aid of the means, instruments, methods and processes described in Part 8, chapters 76-93. The corresponding literature descriptions are hereby incorporated by reference and are considered part of the present disclosure.

  A particular substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of general formula I to be administered to a patient, optionally in its racemate, in its pure stereoisomer, in particular enantiomer or diastereo Or mixtures of stereoisomers in any desired mixing ratio, in particular enantiomers, diastereomers and / or rotamers, or in each case the corresponding salts, in particular physiologically acceptable salts, or corresponding solvates. The amount of the substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide, particularly in the form of a hydrate, can vary and includes, for example, the weight or age of the patient, and the mode of administration, signs of illness and Depends on severity. Conventionally, at least one substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of the general formula I, optionally in its racemic form, in its pure stereoisomers, in particular in enantiomers or diamides. Stereomers, or mixtures of stereoisomers in any desired mixing ratio, in particular enantiomers or diastereomers, or in each case the corresponding salts, in particular physiologically acceptable salts, or the corresponding solvates, in particular hydrates. The substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide in the form of is administered in an amount of 0.005 to 500 mg / kg (patient weight), preferably 0.05 to 50 mg / kg (patient weight).

Pharmacological method:
a) Method for determining affinity for human mu opioid receptor The affinity for human mu opioid receptor is determined in a homogeneous batch in a microtiter plate. For this purpose, a dilution series of the particular substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide to be tested of general formula I is prepared in human μ opioid receptor (in a total volume of 250 μl for 90 minutes at room temperature). With CHO-K1 cell receptor membrane preparations (μ opiate receptor) (15-40 μg protein per 250 μl incubation batch) (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium), 1 nmol / l of radioligand [ ³ H] -naloxone (from NET719, Naven in Zaventem, Belgium) and 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads, Germany, Freiburg, Amersham / Pharmace Incubate in the presence of shea (from Amersham / Pharmacia, Freiburg, Germany). The incubation buffer used is 50 mmol / l Tris-HCl supplemented with 0.05 wt.% Sodium azide and 0.06 wt.% Bovine serum albumin. An additional 25 μmol / l naloxone was added to determine non-specific binding. Once the 90 minute incubation period has passed, the microtiter plate is centrifuged at 1000 g for 20 minutes and the radioactivity is obtained from a β-counter (PerkinElmer Wallac, Freiburg, Germany). ] Was measured. The percentage of radioligand transferred from its binding position to the human μ opiate receptor is determined at a concentration of 1 μmol / l of the compound to be tested and is the percent inhibition of specific binding. Based on the percentage migration of the compound to be tested of general formula I with different concentrations, the IC ₅₀ inhibitory concentration that resulted in approximately 50% migration of the radioligand was calculated. The K _i value for the test substance can be obtained by conversion using the Cheng-Prusoff equation.

b) Method for determining noradrenaline and 5-HT uptake inhibition:
Synaptosomes from the rat brain region have been described in the publication “The isolation of nerve endings from brain”, EG Gray and VP Whittaker, J. Anatomy 96, 79-88, 1962, for in vitro studies. Isolate freshly. The corresponding literature descriptions are hereby incorporated by reference and are considered part of the present disclosure.

  Teflon® tissue (hypothalamic for determining noradrenaline uptake and bone marrow and pons for determining 5-HT uptake) in ice-cold 0.32M sucrose (tissue 100 mg / 1 ml) ) Homogenize in a glass homogenizer with a pestle using 5 full up / down strokes at 840 rpm.

The homogenate is centrifuged at 1000 g for 10 minutes at 4 ° C. After subsequent centrifugation at 17000 g for 55 minutes, synaptosomes (P ₂ fraction) are obtained and resuspended in 0.32 M glucose [0.5 ml / 100 mg (original weight)].

Specific intake is measured in a 96-well microtiter plate. The volume is 250 μl and the incubation proceeds in an O ₂ atmosphere at room temperature (approximately 20-25 ° C.).

Incubation times are 7.5 minutes for [ ³ H] -NA and 5 minutes for [ ³ H] -5-HT. The 96 samples are then filtered through Unifilter GF / B® microtiter plates (Packard) and washed with 200 ml of incubated buffer using a “Brabdel MPXRI-96T cell harvester (Cell-Harvester)” . The Unifilter GF / B plate is dried for 1 hour at 55 ° C. The plate is then sealed with Back seal® (Packard) and 35 μl of scintillation fluid per well is added [Ultima Gold®, Packard]. After sealing with top seal® (Packard) and establishing equilibrium (about 5 hours), the radioactivity is determined in “Trilux 1450 Microbeta” (Wallac).

  The amount of protein used in the above determination is, for example, as described in “Protein measurement with the folin phenol reagent”, Lowry et al., J. Biol. Chem., 193, pages 265-275, 1951. Corresponds to values known from the literature.

  A detailed description of the above method is further described in the literature, for example M. Ch. Frink, H.-H. Hennies, W. Engelberger, M. Haurand and B. Wilffert, (1996) Arzneim.-Forsch./Drug Res. 46 ( III), 11, 1029-1036.

  The corresponding literature description in each case is included herein by reference and is considered part of the present disclosure.

The following properties were determined for NA or 5-HT transporters:
NA intake: Km = 0.32 ± 0.11μM
5HT intake: Km = 0.084 ± 0.011μM

c) Study of analgesic efficacy by agony test The study on the analgesic efficacy of the compounds of the present invention of general formula I was performed following IC Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. There. 125, 237-240. Perform by phenylquinone-induced agony in modified mice. The corresponding literature descriptions are hereby incorporated by reference and are considered part of the present disclosure.

  Male NMRI mice weighing 25-30 g were used for this purpose. A group of 10 animals receives the compound dose, and 10 minutes after the compound to be tested is administered intravenously, 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Desenhofen, Germany; 5 ethanol) Solution prepared in a water bath at 45 ° C. and 0.3 ml / mouse is administered intraperitoneally. The animals are individually placed in an observation basket. Use a push button counter to record the number of stretching exercises (painful reaction = straightening the torso while stretching the hind legs) induced by pain for 5-20 minutes after administration of phenylquinone . Controls were provided by animals that received only physiological saline solution. All compounds were tested at a standard dose of 10 mg / kg.

  The invention is described below with reference to examples. These descriptions are merely examples and do not limit the general concept of the invention.

NMR spectra were measured on a Bruker DPX 300 instrument for the 300 MHz spectrum and on a Bruker DRX 600 instrument for the 600 MHz spectrum.
Certain chemicals and solvents were purchased from conventional manufacturers.

A)
General synthetic method for preparing compounds of general formula II:
A specific 1H-methyl-pyrrole-2-carboxylic acid (50 mmol) of the general formula IV (wherein R ³ represents a methyl group in each case) was suspended in 200 ml of toluene. Next, while cooling with an ice bath, 100 mmol of sodium hydride (NaH) was added slowly and the mixture was stirred for approximately 10 minutes at room temperature. After adding 200 mmol of oxalyl chloride, the reaction mixture was refluxed for 15 minutes and then excess oxalyl chloride and the reaction medium were removed on a rotary evaporator.
The resulting residue was redissolved in 200 ml of diethyl ether and slowly combined with 100 mmol of the corresponding amine of general formula NHR ⁴ R ⁵ and the resulting reaction mixture was refluxed for 2 hours. After cooling, the reaction mixture was washed 3 times with 50 ml portions of water. The organic phase was separated, dried over magnesium sulphate and evaporated on a rotary evaporator. The obtained crude product was used in the next synthesis step without further purification.

  The compounds of general formula II prepared by the general synthesis method described above are listed in Table 1 below:

[1]:一般式IIの化合物

[1]: Compound of general formula II

The structures of compounds II-1 to II-6 were determined by ¹ H-NMR spectroscopy in each case. The chemical shift of the selected compound is shown below.

II-1 1-methyl-1H-pyrrole-2-carboxylic acid dibenzylamide δ (DMSO, 300 MHz) = 3.73 (s, 3 H, NCH ₃ ); 4.58-4.72 (m, 4 H, CH ₂ Ph) 5.95 (dd, 1 H, J = 2.6 Hz, J = 6.0 Hz, N (CH ₃ )]-CHCHCHC- [); 6.23-6.29 (m, 1 H, N (CH ₃ )-]-CHCHCHC- [ ); 6.88-6.93 (m, 1 H, N (CH ₃ )-]-CHCHCHC- [); 7.16-7.42 (m, 10 H, Ph).

II-2 (1-Methyl-1H-pyrrol-2-yl) -piperidin-1-ylmethanone δ (DMSO, 300 MHz) = 1.45-1.68 (m, 6 H, N-[(CH ₂ ) ₂ -CH ₂ -(CH ₂ ) _2- [); 3.51-3.62 (m, 4 H, N-[(CH ₂ ) ₂ -CH _2- (CH ₂ ) _2- [); 3.65 (s, 3 H, NCH ₃ ) 5.97-6.03 (m, 1 H, N (CH ₃ )-]-CHCHCHC- [); 6.21-6.25 (m, 1 H, N (CH ₃ )]-CHCHCHC- [); 6.79-6.84 (m, 1 H, N (CH ₃ )]-CHCHCHC- [).

II-4 1-methyl-1H-pyrrole-2-carboxylic acid benzylmethylamide δ (DMSO, 300 MHz) = 2.99 (br. S, 3 H, NCH ₃ Bn); 3.71 (s, 3 H, NCH ₃ ) 4.65-4.75 (m, 2 H, CH ₂ Ph); 5.96-6.04 (m, 1 H, N (CH ₃ )]-CHCHCHC- [); 6.28-6.41 (m, 1 H, N (CH ₃ ) -] - CHCHCHC- [); 6.87 - 6.93 (m, 1 H, N (CH 3) -] - CHCHCHC- [); 7.18 - 7.43 (m, 5 H, Ph).

II-5 1-methyl-1H-pyrrole-2-carboxylic acid benzylisopropylamide δ (DMSO, 300 MHz) = 1.15 (d, 3 H, J = 6.8 Hz, CH (CH ₃ ) ₂ ); 3.67 (s, 3 H, NCH ₃ ); 4.52-4.67 (m, 3 H, CH ₂ Ph, CH (CH ₃ ) ₂ ); 5.95-6.03 (m, 1 H, N (CH ₃ )]-CHCHCHC- [); 6.25 -6.34 (m, 1 H, N (CH ₃ )-]-CHCHCHC- [); 6.80-6.86 (m, 1 H, N (CH ₃ )-]-CHCHCHC- [); 7.15 -7.36 (m, 5 H, Ph).

II-6 1-methyl-1H-pyrrole-2-carboxylic acid cyclohexylmethylamide δ (DMSO, 300 MHz) = 0.88-1.36 (m, 4 H, N] -CH (CH ₂ ) ₂ (CH ₂ ) ₂ CH _2- [); 1.44-1.85 (m, 6 H, N] -CH (CH ₂ ) ₂ (CH ₂ ) ₂ CH _2- [); 2.88 (s, 3 H, N-CH ₃ ); 3.64 (s , 3 H, NCH ₃ ); 4.03-4.19 (m, 1 H, N] -CH (CH ₂ ) ₂ (CH ₂ ) ₂ CH _2- [); 5.97-6.04 (m, 1 H, N (CH ₃ )] - CHCHCHC- [); 6.19 - 6.29 (m, 1 H, N (CH 3)] - CHCHCHC- [); 6.79 - 6.85 (m, 1 H, N (CH 3)] - CHCHCHC- [).

B)
General procedure for the automated synthesis of compounds of general formula I according to the invention. The synthesis was performed with an automatic synthesizer made by Zymark.
Batch amount Aminal of general formula V 300μmol
300 μmol of pyrrole of general formula II
600 μmol acetyl chloride
Pipette volume Aminal solution 1 ml
1 ml of pyrrole solution
0.6 ml of acetyl chloride solution
Stock solution 0.3M aminal solution in CH ₃ CN (Solution I)
0.3M pyrrole solution in CH ₃ CN (Solution II)
1M acetyl chloride solution in CH ₃ CN (Solution III)

Perform synthesis:
300 μmol of the aminal compound of general formula V (solution I, 1 ml) was first introduced into a dry threaded glass vial with a diaphragm cap at 20 ° C. and combined with 600 μmol of acetyl chloride (solution III, 0.6 ml). After 1 hour, 300 μmol of pyrrole derivative of general formula II (solution II, 1 ml) was added by pipette. The reaction solution was stirred at 20 ° C. for 24 hours. 2 ml of HCl solution (0.1 M) and 2 ml of CH ₂ Cl ₂ were then added at the quench station. The resulting solution was mixed in a rotary reactor for 30 minutes. The magnetic stir bar was removed and the vessel was washed with ₂ ml CH ₂ Cl ₂ .

Synthetic work-up:
The lower organic phase was removed and discarded. 4 ml of CH ₂ Cl ₂ was added to the vortexer and then mixed in the rotary reactor for another 10 minutes. After centrifugation, the organic phase was removed again and discarded, the aqueous phase was once again combined with 4 ml of CH ₂ Cl ₂ and adjusted to pH 8-9 with 0.7 ml of 7.5% strength NaHCO ₃ solution. The solution was mixed vigorously in a rotary reactor and after centrifugation, the organic phase was separated and collected. The aqueous phase was extracted once again with 4 ml of CH ₂ Cl ₂ . The combined organic phases were then dried over MgSO ₄ cartridge and evaporated under reduced pressure. Further purification of the compound was performed by preparative HPLC.

The following compounds of the invention of general formula I were prepared in this way:
Example 1:
1-Methyl-5- (4-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzyl-methylamide
MS: (ESI) m / z = 339 [M + + 1]; 241.

Example 2:
5-Azepan-1-ylmethyl-1-methyl-1H-pyrrol-2-yl) -pyrrolidin-1-ylmethanone
MS: (ESI) m / z = 290 [M + + 1]; 219; 191.

Example 3:
1-Methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrol-2-yl] -pyrrolidin-1-ylmethanone
MS: (ESI) m / z = 290 [M + + 1]; 191.

Example 4:
1-Methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carboxylic acid benzylamide
MS: (ESI) m / z = 312 [M + + 1]; 241.

Example 5:
1-Methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzyl-methylamide
MS: (ESI) m / z = 340 [M ⁺ +1];

Example 6:
1- (5-Dibenzylcarbamoyl-1-methyl-1H-pyrrol-2-ylmethyl) -piperidine-4-carboxylic acid ethyl ester
MS: (ESI) m / z = 475 [M ⁺ +1]; 317; 198.

Example 7:
5- (4-Benzyl-piperidin-1-ylmethyl) -1-methyl-1H-pyrrole-2-carboxylic acid cyclohexyl-methylamide
MS: (ESI) m / z = 409 [M ⁺ +1];

Example 8:
[5- (4-Benzyl-piperidin-1-ylmethyl) -1-methyl-1H-pyrrol-2-yl] -piperidin-1-ylmethanone
MS: (ESI) m / z = 381 [M ⁺ +1];

Example 9:
1-Methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzyl-isopropylamide
MS: (ESI) m / z = 368 [M ⁺ +1];

Example 10:
[1-Methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrol-2-yl] -piperidin-1-ylmethanone
MS: (ESI) m / z = 304 [M + + 1]; 205.

Pharmacological studies:
a) Affinity for μ receptor The affinity of the 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide of the present invention for the μ receptor was determined as described above. The values for some selected compounds are shown in Table 1 below.

b)5-HT摂取阻害及びノルアドレナリン(NA)摂取阻害

b) Inhibition of 5-HT intake and noradrenaline (NA) intake

  Inhibition of 5-HT reuptake and noradrenaline reuptake of 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of the present invention was determined as described above. The values for some selected compounds are shown in Table 2 below.

[2] 5-HT摂取、ラット、10μM、阻害％
[3] NA摂取、ラット、10μM、阻害％

[2] 5-HT intake, rat, 10 μM,% inhibition
[3] NA intake, rat, 10 μM,% inhibition

Claims (14)

Substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amides of general formula I:

(Where
R ¹ and R ² together with the nitrogen atom connecting them as ring members form a pyrrolidinyl, piperidinyl, or azepanyl residue, these residues being the same or different selected from the group consisting of methyl, ethoxycarbonyl and benzyl May be mono- or polysubstituted with substituents ,
R ³ represents a methyl group ,
R ⁴ represents a methyl, iso-propyl, cyclohexyl, or benzyl group ,
R ⁵ represents a methyl, iso-propyl, cyclohexyl or benzyl group ,
Or
R ⁴ and R ⁵ together with the nitrogen atom connecting them as ring members form a pyrrolidinyl or piperidinyl residue)
A is in each case optionally their pure stereoisomers, their racemates, or mixtures of steric isomers, or in each case in the form of corresponding salts, or in each case, the corresponding solvent The above substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide, which may be in the form of a hydrate.   The compound according to claim 1, wherein the stereoisomer is an enantiomer or a diastereomer, and the mixture of stereoisomers is a mixture of enantiomers, diastereomers and / or rotamers. 3. A compound according to claim 1 or 2 selected from the group consisting of:
1-methyl-5- (4-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzylmethylamide,
(5-azepan-1-ylmethyl-1-methyl-1H-pyrrol-2-yl) -pyrrolidin-1-ylmethanone,
[1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrol-2-yl] -pyrrolidin-1-ylmethanone,
1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carboxylic acid benzylmethylamide,
1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzyl-methylamide,
1- (5-dibenzylcarbamoyl-1-methyl-1H-pyrrol-2-ylmethyl) -piperidine-4-carboxylic acid ethyl ester,
5- (4-benzyl-piperidin-1-ylmethyl) -1-methyl-1H-pyrrole-2-carboxylic acid cyclohexylmethylamide,
[5- (4-benzyl-piperidin-1-ylmethyl) -1-methyl-1H-pyrrol-2-yl] -piperidin-1-ylmethanone,
1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrole-2-carboxylic acid benzylisopropylamide, and
[1-methyl-5- (2-methyl-piperidin-1-ylmethyl) -1H-pyrrol-2-yl] -piperidin-1-ylmethanone,
Here, in each case, in some cases their pure stereoisomers, their racemates, or in the form of a mixture of steric isomers, or in each case in the form of corresponding salts, or in each case, the corresponding It may be in the form of a solvate. A process for producing a substituted 5-aminomethyl-1H-pyrrole-2-carboxylic acid amide according to any one of claims 1 to 3 , wherein the substituted 1H-pyrrole-2-carboxylic acid amide of the general formula II:

(Wherein residues R ^3, R ⁴ and R ⁵ have the meanings placing serial to claim 1), iminium salts of the general formula III:

Wherein to no R ¹ R ² has the meaning of mounting serial to claim 1, and A ^- is _{^{Cl -, AlCl 4 -, Br}} -, I - or CF ₃ -SO ₃ ^- (triflate anion) is reacted with the shown], purified in some cases the compound obtained, and manufacturing method characterized by isolating some cases. A pharmaceutical formulation comprising at least one compound according to any one of claims 1 to 3 and optionally one or more physiologically acceptable auxiliary substances. The pharmaceutical preparation according to claim 5, for regulating 5-hydroxytryptamine (5-HT) intake. 6. A pharmaceutical formulation according to claim 5 for regulating noradrenaline (NA) uptake. 6. A pharmaceutical formulation according to claim 5 for the modulation of opioid receptors. 9. A pharmaceutical formulation according to any one of claims 5 to 8 for treating pain. The pharmaceutical preparation according to claim 9 , for treating pain selected from the group consisting of chronic pain, acute pain and neuropathic pain. Use of at least one compound according to any one of claims 1 to 3 for the manufacture of a pharmaceutical formulation for regulating 5-hydroxytryptamine (5-HT) uptake. Use of at least one compound according to any one of claims 1 to 3 for the manufacture of a pharmaceutical formulation for regulating noradrenaline (NA) uptake. Use of at least one compound according to any one of claims 1 to 3 in the manufacture of a pharmaceutical formulation for the modulation of opioid receptors. Use of at least one compound according to any one of claims 1 to 3 for the manufacture of a pharmaceutical preparation for the treatment of pain.